CBMT-42. LOSS OF PROMOTER METHYLATION IN GLYCOLYTIC GENES IS ASSOCIATED WITH AGGRESSIVENESS IN IDH1-MUTANT LOWER GRADE GLIOMAS. (5th November 2018)

• Record Type: Journal Article
• Authors: Larion, Mioara; Rodado, Victor Ruiz; Seki, Tomohiro; Malta, Tathiane; Lita, Adrian; Dowdy, Tyrone; Celiku, Orieta; Saldana, Alejandra Cavazos; Li, Aiguo; Zhang, Wei; Song, Hua; Davis, Dionne; Lee, Sunmin; Neckers, Jane; Munasinghe, Jeeva; Noushmehr, Houtan; Herold-Mende, Christel; Gilbert, Mark; Cherukuri, Murali Krishna
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 6
• Page Start: vi41
• Page End: vi42
• Publication Date: 2018-11-05
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy148.161
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: BACKGROUND: Identification of malignant progression is a major challenge in the field of Neuro-Oncology because of inability of traditional imaging methods to distinguish pseudo-progression from true progression. IDH1-mutant gliomas represent an ideal model system to study the molecular mechanisms associated with malignant progression because they appear initially indolent and non-glycolytic, but eventually a subset progress towards secondary glioblastoma with a Warburg-like phenotype. The mechanisms and molecular features associated with this transformation are poorly understood. METHODS: TS603, NCH1681 and BT142 cell lines harboring IDH1 mutation were cultured in DMEM/F12+ N2 supplement, glutamine, FGF and EGF, then either harvested for metabolomics and methylation analyses or (250, 000 cells) were injected into 6-week-old SCID mice brains. MRI was used to monitor tumor size; when tumors reached 100 mm 3, mice were injected in the tail vain with 96 mM 1- 13 C pyruvate which was hyperpolarized using Oxford Hypersense hyperpolarizer and chemical shift images were acquired immediately. Metabolite quantification was done using the Agilent LC/MS 6545 QTOF mass spectrometer. DNA methylation analysis was performed using Ilumina Infinium MethylationEPIC. RESULTS AND CONCLUSIONS: Cell lines that demonstrate aggressive growth both in vitro and in vivo have lost methylation in the promoters of glycolytic enzymes and have increased mRNA and metabolite levels for the glycolysis pathway compared to the non-transformed model. Metabolic 13 C MRI using hyperpolarized 13 C pyruvate confirmed that these aggressive lines have a Warburg-like phenotype (aerobic glycolysis). Moreover, the glycolytic enzyme expression of the aggressive cell line correlated with the subset of patients that are IDH1 mutated and low-G-CIMP in TCGA database. We hypothesize that specific modulation of epigenetic markers is a mechanism of malignant transformation and that monitoring lactate production may be a biomarker of transformation.